P520: PHASE 1/2 STUDY OF SEL24/MEN1703, A FIRST-IN-CLASS DUAL PIM/FLT3 KINASE INHIBITOR, IN PATIENTS WITH IDH1/2-MUTATED ACUTE MYELOID LEUKEMIA: THE DIAMOND-01 TRIAL.
Authors: G. Martinelli, A. Santoro, C. Gambacorti-Passerini, S. Vives Polo, S. R. Solomon, S. Mukherjee, E. Lech-Maranda, M. Yair Levy, A. Wierzbowska, M. Calbacho-Robles, G. Marconi, M. Benedetta Giannini, I. Cano, L. Torres Miñana, E. Acuña-Cruz, N. Angelosanto, A. Galleu, S. Baldini, S. Blotta, F. Ravandi, P. Montesinos
Journal: HemaSphere (2022)

Background: Mutations in the FLT3 tyrosine kinase are the most frequent mutations that occur in adults with acute myeloid leukemia (AML) and can co-occur with mutations in IDH1 or IDH2 (collectively IDHm) in up to 30% of cases. SEL24/MEN1703 is an orally available, first-in-class, dual PIM/FLT3 kinase inhibitor. Preliminary results from the phase 1/2 first-in-human DIAMOND-01 trial (NCT03008187) evaluating single-agent SEL24/MEN1703 showed activity in adults with relapsed/refractory (R/R) IDHm AML, where 3 of 8 IDHm patients responded. Aims: Here we report the first safety and efficacy results from an additional expansion cohort of the DIAMOND-01 trial in 20 patients with R/R IDHm AML. Methods: Patients with IDHm R/R AML and no standard therapeutic options were eligible. The recommended dose of 125 mg SEL24/MEN1703 was given orally, once daily for 14 days over a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was safety, and adverse events (AEs) were graded according to NCI CTCAE v4.03. The secondary endpoint was antileukemic activity including overall response rate (ORR). Results: As of 10 January 2022, 14 patients were enrolled in the IDHm cohort. Median age was 68 years (range 37–79). Four patients had AML secondary to myelodysplastic syndrome and 7 patients had intermediate cytogenetic risk. Median number of prior lines of treatment was 2 (range 1–3). Seven patients had IDH2, 1 had IDH1/2, and 4 had IDH1 mutations. Concomitant mutations in FLT3-ITD were detected in 2 patients. Median duration of treatment was 2 cycles (range 1–8). Safety data (N=12) showed that serious treatment-emergent AEs (TEAEs; reported in ≥5% patients) were pneumonia (33%), skin infection, and clostridial gastroenteritis (8% each). These events were all unrelated to study drug. Drug-related TEAEs were liver injury and hyponatremia (8% each). The drug-related liver injury occurred in a patient who was concomitantly receiving other drugs with known hepatotoxic potential. Grade ≥3 TEAEs (≥10% patients) were pneumonia (33%) and asthenia (17%), both unrelated to study drug. No differentiation syndrome was observed. Of the 7 patients who completed ≥1 treatment cycle and had ≥1 postbaseline assessment or clear disease progression, ORR was 28.6%; 1 patient achieved a complete response with incomplete blood count recovery (CRi) at cycle 3 and underwent hematopoietic stem cell transplant, 1 patient had a partial response at cycle 4 (confirmed at cycle 7 and still on treatment), 4 had disease progression, and 1 discontinued for an AE (not drug related). Among the 7 remaining patients, 3 discontinued before completion of cycle 1 without progression or response, while 4 patients were ongoing and have not yet had any postbaseline assessment. Summary/Conclusion: Preliminary results in the IDHm cohort confirm that SEL24/MEN1703, a first-in-class, orally available, dual PIM/FLT3 inhibitor, has a manageable safety profile and single-agent activity in patients with R/R IDHm AML. Updated results will be presented at the congress.